TRP CHANNEL EXPRESSION AND FUNCTION IN ON-BIPOLAR CELLS
Lane Ronald
Oregon Health And Science Universitycity: Portland country: United States (us)
Grant 5R01EY019907-03 from National Eye Institute
Keywords: ing; Affect; Apical; base; Biochemical; Blindness; Cations; Cells; Complex; Coupled; Darkness; Data; Defect; Dendrites; Disease; Electrophysiology (science); Electroretinography; Equus caballus; Eye; Eye diseases; Eye Movements; Family; Gated Ion Channel; Gene Expression Profiling; gene function; Genes; Genetic; Glutamate Receptor; Glutamates; Go Alpha Subunit; Goals; GRM6 gene; GTP-Binding Proteins; Hyperopia; image processing; Immunohistochemistry; In Situ Hybridization; In Vitro; in vivo; Inherited; insight; Ion Channel; Light; light intensity; Lighting; Macaca; Measures; Mediating; member; Metabotropic Glutamate Receptors; Molecular; Molecular Genetics; mouse model; Mus; mutant; Mutation; Myopia; Night Blindness; null mutation; patch clamp; Pathologic Nystagmus; Pathology; Pathway interactions; Pharmacology; Phenotype; Photoreceptors; Physiological; Physiology; postsynaptic; Property; receptor; Reporting; Research; response; Rest; Retina; Retinal; Retinal Cone; Retinal Diseases; Reverse Transcriptase Polymerase Chain Reaction; RNA Splicing; Rods (Retina); Shapes; Signal Pathway; Signal Transduction; Staging; Symptoms; Synapses; Synaptic Transmission; Testing; Variant; Vision; Visual; Visual Acuity; visual information; Visual Pathways; visual process; visual processing; Visual system structure; Work
Relevance: Congenital stationary night blindness (CSNB) is an inherited eye disorder causing night blindness, and also often shortsightedness, nystagmus (involuntary eye movement), and reduced visual acuity, even under normal lighting conditions. The proposed research will determine if abnormal ion channel function in the eye can be a cause of CSNB
Project start date: 2010-01-01
Project end date: 2012-12-31
Budget start date: 1-JAN-2012
Budget end date: 31-DEC-2012
5R01EY019907-03 (2012): $411037
Sponsored Links Excellgen http://Excellgen.com
TRP CHANNEL EXPRESSION AND FUNCTION IN ON-BIPOLAR CELLS
Lane Ronald, Associate Professor
Oregon Health And Science Universitycity: Portland country: United States (us)
Grant 5R01EY019907-02 from National Eye Institute
Abstract: Congenital stationary night blindness (CSNB) is a group of non-progressive retinal diseases characterized by impaired scotopic vision. Mutations in a number of genes have been shown to be associated with CSNB. They generally affect synaptic transmission between photoreceptors and the second order bipolar cells. When the mutant gene is expressed only in rods, or rod bipolar cells, the phenotype is limited to night blindness. However, when the mutant gene function is also required for synaptic transmission between cones and cone bipolar cells, further visual symptoms are apparent such as myopia, hyperopia, nystagmus, and reduced visual acuity. One such example are mutations in GRM6, the gene encoding mGluR6, which cause an autosomal recessive form of CSNB. In the retina, visual information is segregated into pathways that respond to increases and decreases in light intensity. At the first retinal synapse, the tonic release of glutamate from photoreceptor terminals maintains a high synaptic concentration in darkness that decreases in response to light. Two types of postsynaptic cells, the ON- and OFF-bipolar cells, respond with opposite polarity to glutamate released by photoreceptors, thus establishing the opposing visual pathways. The basis of signaling in OFF-bipolar cells, which relies on the activation of ionotropic glutamate receptors, is well understood. The signaling pathway that generates the light response in ON-bipolar cells, however, is more complex, and the molecular mechanisms remain to be elucidated. The ON-bipolar cell signaling pathway originates with a unique metabotropic glutamate receptor, mGluR6, which is found on the dendrites of ON-bipolar cells. mGluR6 acts via a G-protein, Go, to regulate the activity of an unidentified cation channel such that the light-induced decrease in synaptic glutamate opens the channel and depolarizes the cell. Recently, it has been reported that CSNB in Appaloosa horses is associated with a mutation causing a reduced expression of the TRPM1 cation channel. We hypothesize that TRPM1, and possibly other related TRP channels, are the cation channels coupled to mGluR6 that mediate the depolarizing light response of ON-bipolar cells. We further suggest that mutations in TRP channels will cause CSNB. Using a combination of biochemical, immunohistochemical, and electrophysiological approaches, we will test this hypothesis by answering the following questions 1. Which TRP channel variants are expressed in ON-bipolar cells? 2. Do mice that carry null mutations in TRP channels expressed in bipolar cells have CSNB? 3. Can the physiological and pharmacological properties of retinal ON bipolar cell responses be reproduced in transfected HEK cells expressing the proper combination of TRP channel variants? The data from this study will contribute to the elucidation of the signaling pathway in the ON-bipolar cell, a fundamental, yet poorly understood, step in visual processing. Congenital stationary night blindness (CSNB) is an inherited eye disorder causing night blindness, and also often shortsightedness, nystagmus (involuntary eye movement), and reduced visual acuity, even under normal lighting conditions. The proposed research will determine if abnormal ion channel function in the eye can be a cause of CSNB
Keywords: Affect; Apical; base; Biochemical; biological signal transduction; Blindness; Cations; Cell Communication and Signaling; Cell Signaling; Cell/Tissue, Immunohistochemistry; Cells; Complex; Cone; cone cell; Cones (Eye); Cones (Retina); Coupled; Darkness; Darknesses; Data; Defect; Dendrites; Disease; disease/disorder; Disorder; Electrophysiology; Electrophysiology (science); electroretinogram; Electroretinography; Equine; Equine Species; Equus caballus; Equus przewalskii; Eye; Eye diseases; eye disorder; Eye Movements; Eyeball; Family; Farsightedness; G Protein Go; G(o) Protein; G-Protein, Go Subunit; G-Protein, Inhibitory Go; Gated Ion Channel; Gene Expression Monitoring; Gene Expression Pattern Analysis; Gene Expression Profiling; gene function; Genes; Genetic; Genetic Alteration; Genetic Change; Genetic defect; Genetics, in situ Hybridization; genome mutation; Glutamate Receptor; Glutamates; Go Alpha Subunit; Goals; GPRC1F; GRM6; GRM6 gene; GTP Binding Protein alpha Subunit, Go; Guanine Nucleotide-Binding Protein Go; Hereditary; Horse, Domestic; Horses; Hypermetropia; Hyperopia; IHC; Illumination; image processing; Immunohistochemistry; Immunohistochemistry Staining Method; In Situ Hybridization; in situ Hybridization Staining Method; In Vitro; in vivo; Inherited; insight; Intracellular Communication and Signaling; Ion Channel; Ionic Channels; L-Glutamate; Light; light intensity; Lighting; Macaca; Macaque; Mammals, Mice; Measures; Mediating; member; Membrane Channels; Metabotropic Glutamate Receptors; mGlu6; MGLUR6; Mice; Molecular; Molecular Genetic; Molecular Genetics; mouse model; Murine; Mus; mutant; Mutation; Myopia; near vision; Nearsightedness; Nearsightednesses; Neural Transmission; Neurophysiology / Electrophysiology; Night Blindness; null mutation; Nyctalopia; nystagmus; Nystagmus, Pathologic; ophthalmopathy; patch clamp; Pathologic Nystagmus; Pathology; pathway; Pathway interactions; Pharmacology; Phenotype; Photoradiation; Photoreceptor Cell; Photoreceptors; Photoreceptors, Cone; Photosensitive Cell; Physiologic; Physiological; Physiology; postsynaptic; Profilings, Gene Expression; Property; Property, LOINC Axis 2; public health relevance; receptor; Receptor Protein; Reporting; Research; response; Rest; Retina; retina disease; retina disorder; Retinal; Retinal Cone; Retinal Diseases; Retinal Disorder; retinopathy; reverse transcriptase PCR; Reverse Transcriptase Polymerase Chain Reaction; RNA Splicing; Rod; rod cell; Rod Photoreceptors; Rods (Eye); Rods (Retina); RT-PCR; RTPCR; Shapes; Sight; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Splicing; Staging; Symptoms; Synapses; Synaptic; Synaptic Transmission; Testing; Transcript Expression Analyses; Transcript Expression Analysis; Variant; Variation; Vision; Visual; Visual Acuity; visual information; Visual Pathways; visual process; visual processing; Visual Receptor; Visual System; Visual system structure; Work
Relevance: Congenital stationary night blindness (CSNB) is an inherited eye disorder causing night blindness, and also often shortsightedness, nystagmus (involuntary eye movement), and reduced visual acuity, even under normal lighting conditions. The proposed research will determine if abnormal ion channel function in the eye can be a cause of CSNB
Project start date: 2010-01-01
Project end date: 2012-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-07-070
5R01EY019907-02 (2011): $416601